Gene Targeting on Point: Targeted Delivery of Tumor Suppressor Gene CHRDL‐1 via Peptide/FA‐Modified Layered Double Hydroxides Partner With JPH203 for Effective Hepatocellular Carcinoma Inhibition

Abstract The incidence of hepatocellular carcinoma (HCC) is increasing worldwide annually. However, traditional treatments like surgery, targeted therapy, and immunotherapy have limited efficacy, often accompanied by adverse reactions or drug resistance. Precision therapy via tumor‐specific gene therapy and targeted delivery would potentially improve therapeutic efficiency with desirable biosafety. In this study, CHRDL‐1 is identified in clinic specimens and comprehensively evaluated as a tumor suppressor gene against HCC via activation of the Hippo pathway. By integrating pDNA‐CHRDL‐1, layered double hydroxides, membrane‐penetrating peptide and folic acid, a novel nano‐platform (FT‐BL@P) is designed for HCC‐targeted gene therapy. As prepared FT‐BL@P effectively suppress the growth of HCC cells and induces apoptosis both in vitro and in vivo. Combined with JPH203, a phase 2 L‐type amino acid transporter 1 (LAT‐1) inhibitor, FT‐BL@P achieves synergistic anti‐tumor effects in a xenograft HCC model, suggesting that the co‐delivery of CHRDL‐1 combined with JPH203 holds promise as a potential therapeutic strategy for HCC.